Defective intracellular Ca2+ signaling contributes to cardiomyopathy in Type 1 diabetic rats

2002 ◽  
Vol 283 (4) ◽  
pp. H1398-H1408 ◽  
Author(s):  
Kin M. Choi ◽  
Yan Zhong ◽  
Brian D. Hoit ◽  
Ingrid L. Grupp ◽  
Harvey Hahn ◽  
...  
Keyword(s):  
Diabetic Rats ◽  
Diabetic Rat ◽  
Channel Current ◽  
Voltage Dependent ◽  
Intracellular Ca ◽  
Rat Myocytes ◽  
Systolic And Diastolic Function ◽  
And Function ◽  
Contraction And Relaxation

The goal of the study was to determine whether defects in intracellular Ca2+ signaling contribute to cardiomyopathy in streptozotocin (STZ)-induced diabetic rats. Depression in cardiac systolic and diastolic function was traced from live diabetic rats to isolated individual myocytes. The depression in contraction and relaxation in myocytes was found in parallel with depression in the rise and decline of intracellular free Ca2+ concentration ([Ca2+]i). The sarcoplasmic reticulum (SR) Ca2+ store and rates of Ca2+ release and resequestration into SR were depressed in diabetic rat myocytes. The rate of Ca2+ efflux via sarcolemmal Na+/Ca2+ exchanger was also depressed. However, there was no change in the voltage-dependent L-type Ca2+ channel current that triggers Ca2+ release from the SR. The depression in SR function was associated with decreased SR Ca2+-ATPase and ryanodine receptor proteins and increased total and nonphosphorylated phospholamban proteins. The depression of Na+/Ca2+ exchanger activity was associated with a decrease in its protein level. Thus it is concluded that defects in intracellular Ca2+ signaling caused by alteration of expression and function of the proteins that regulate [Ca2+]i contribute to cardiomyopathy in STZ-induced diabetic rats. The increase in phospholamban, decrease in Na+/Ca2+ exchanger, and unchanged L-type Ca2+ channel activity in this model of diabetic cardiomyopathy are distinct from other types of cardiomyopathy.

scholarly journals Supplementation of Type 1 Diabetic Rats with Carrot Powder Lowers Blood Glucose without Improving Cardiac Structure and Function

2018 ◽  
Vol 23 (2) ◽  
pp. 115-121
Author(s):  
Xavier Lieben Louis ◽  
Pema Raj ◽  
Kathleen J. McClinton ◽  
Liping Yu ◽  
Miyoung Suh ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Diabetic Rats ◽  
Structure And Function ◽  
Cardiac Structure ◽  
Cardiac Structure And Function ◽  
And Function

scholarly journals Curcumin attenuates oxidative stress in liver in Type 1 diabetic rats

2017 ◽  
Vol 12 (1) ◽  
pp. 452-459 ◽  
Author(s):  
Zhenglu Xie ◽  
Xinqi Zeng ◽  
Xiaqing Li ◽  
Binbin Wu ◽  
Guozhi Shen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Polyol Pathway ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Curcumin Treatment ◽  
Kinase C ◽  
Diabetic Model ◽  
Glucose 6 Phosphate Dehydrogenase ◽  
Plasma Malondialdehyde

AbstractWe investigated the effect of curcumin on liver anti-oxidative stress in the type 1 diabetic rat model induced by streptozotocin (STZ). Experimental diabetic rats were induced by STZ intraperitoneally. All rats were fed for 21 days including three groups of control (NC), diabetic model (DC) and curcumin-treated (Cur, 1.5 g/kg by gavage). The results showed that curcumin-treatment significantly decreased the blood glucose and plasma malondialdehyde levels, but significantly increased the plasma superoxide dismutase, glutathione peroxidase and reduced glutathione levels. Curcumin treatment decreased the activity of aldose reductase, but increased the plasma glucose-6-phosphate dehydrogenase, glucose synthetase and glucose-polymerizing activities. Curcumin treatment significantly decreased the protein of protein kinase C (PKC) and poly ADP ribose polymerase (PARP) expression in the Cur group compared with the DC group. Moreover, the sorbitol dehydrogenase activity was significantly decreased and deterred glucose enters into the polyol pathway leading to an increased NADPH content in the Cur group compared with the DC group. Our data provides evidence that oxidative stress in diabetic rats may be attenuated by curcumin by inhibiting polyol pathway associated with down-regulated expression of PKC and PARP, as evidenced by both an increase the antioxidant enzymes levels and glycogen biosynthesis enzymes activities.

Revascularization and Function of Pancreatic Islet Isografts in Diabetic Rats following Transplantation

2003 ◽  
Vol 12 (5) ◽  
pp. 537-544 ◽  
Author(s):  
Hajime Furuya ◽  
Toshihisa Kimura ◽  
Makoto Murakami ◽  
Kanji Katayama ◽  
Kazuo Hirose ◽  
...  
Keyword(s):  
Pancreatic Islet ◽  
Diabetic Rats ◽  
Isolated Islets ◽  
Diabetic Rat ◽  
Pancreatic Islet Transplantation ◽  
Intravenous Glucose ◽  
Lewis Rats ◽  
Group A ◽  
Group B ◽  
And Function

In pancreatic islet transplantation, revascularization is crucial for the graft's survival and function. In this study, the endothelium of isolated islets and revascularization and function of islet isografts in diabetic rat were investigated. Islets were isolated from Lewis rats by collagenase digestion method and were examined using immunohistochemistry (CD31 stain) on days 0, 1, 3, and 7 after isolation. The number of CD31-positive cells in these isolated islets was counted (mean ± SD%). Isografts (freshly isolated islets: group A, and islets cultured for 7 days: group B) transplanted in the renal subcapsule of streptozotocin-induced diabetic Lewis rats were examined using immunohistochemistry (CD31 stain) on days 3, 5, and 7 after transplantation. Intravenous glucose tolerance tests (IVGTT) were performed on days 3 and 7 after transplantation. The number of CD31-positive cells in the isolated islets on days 0, 1, 3, and 7 after isolation were: 17.3 ± 4.1%, 8.2 ± 0.7%, 2.1 ± 0.8%, and 0.8 ± 0.5%, respectively (p < 0.05). On day 5 after transplantation, CD31-positive cells were not detected in group A and B grafts, but were detected in both groups in periphery of the islets. On day 7, CD31-positive microvessels were present throughout the entire graft. IVGTT values in groups A and B on days 3 and 7 after transplantation did not show significant differences. In renal subcapsular isografts in diabetic rats, revascularization into islet grafts occurs from the surrounding host tissue 5 days after transplantation, but has no influence on the response to glucose during this period.

scholarly journals Nicotine Exposure Exacerbates Development of Cataracts in a Type 1 Diabetic Rat Model

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Nima Tirgan ◽  
Gabriela A. Kulp ◽  
Praveena Gupta ◽  
Adam Boretsky ◽  
Tomasz A. Wiraszka ◽  
...  
Keyword(s):  
Rat Model ◽  
Serum Levels ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Positive Trend ◽  
Sprague Dawley ◽  
Nicotine Treatment ◽  
Sprague Dawley Rats ◽  
Diabetic Rat Model

Diabetes and smoking are known risk factors for cataract development. In this study, we evaluated the effect of nicotine on the progression of cataracts in a type 1 diabetic rat model. Diabetes was induced in Sprague-Dawley rats by a single injection of 65 mg/kg streptozotocin. Daily nicotine injections were administered subcutaneously. Forty-five rats were divided into groups of diabetics with and without nicotine treatment and controls with and without nicotine treatment. Progression of lens opacity was monitored using a slit lamp biomicroscope and scores were assigned. To assess whether systemic inflammation played a role in mediating cataractogenesis, we studied serum levels of eotaxin, IL-6, and IL-4. The levels of the measured cytokines increased significantly in nicotine-treated and untreated diabetic animals versus controls and demonstrated a positive trend in the nicotine-treated diabetic rats. Our data suggest the presence of a synergistic relationship between nicotine and diabetes that accelerated cataract formation via inflammatory mediators.

scholarly journals Role of Hyperketonemia in Inducing Oxidative Stress and Cellular Damage in Cultured Hepatocytes and Type 1 Diabetic Rat Liver

2015 ◽  
Vol 37 (6) ◽  
pp. 2160-2170 ◽  
Author(s):  
Preeti Kanikarla-Marie ◽  
Sushil K. Jain
Keyword(s):  
Oxidative Stress ◽  
Liver Damage ◽  
Diabetic Control ◽  
Diabetic Rats ◽  
Cellular Damage ◽  
Diabetic Rat ◽  
Blood Levels ◽  
Per Se ◽  
Rat Livers

Background/Aims: Type 1 diabetic (T1D) patients have a higher incidence of liver disease. T1D patients frequently experience elevated plasma ketone levels along with hyperglycemia. However, no study has examined whether hyperketonemia per se has any role in excess liver damage in T1D. This study investigates the hypothesis that hyperketonemia can induce oxidative stress and cellular dysfunction. Methods: STZ treated diabetic rats, FL83B hepatocytes, and GCLC knocked down (GSH deficient) hepatocytes were used. Results: The blood levels of ALT and AST, biomarkers of liver damage, and ketones were elevated in T1D rats. An increase in NOX4 and ROS along with a reduction in GSH and GCLC levels was observed in T1D rat livers in comparison to those seen in non-diabetic control or type 2 diabetic rats. MCP-1 and ICAM-1 were also elevated in T1D rat livers and ketone treated hepatocytes. Macrophage markers CCR2 and CD11A that interact with MCP-1, and ICAM-1 respectively, were also elevated in the T1D liver, indicating macrophage infiltration. Additionally, activated macrophages increased hepatocyte damage with ketone treatment, which was similar to that seen in GCLC knockdown hepatocytes without ketones. Conclusion: Hyperketonemia per se can induce macrophage mediated damage to hepatocytes and the liver, caused by GSH depletion and oxidative stress up regulation in T1D.

scholarly journals Mitochondrial Perturbation Contributing to Cognitive Decline in Streptozotocin-Induced Type 1 Diabetic Rats

2018 ◽  
Vol 46 (4) ◽  
pp. 1668-1682 ◽  
Author(s):  
Yu Zhou ◽  
Siheng Lian ◽  
Jin Zhang ◽  
Donghai Lin ◽  
Caihua Huang ◽  
...  
Keyword(s):  
Cognitive Decline ◽  
Metabolic Pathways ◽  
Mitochondrial Dynamics ◽  
Diabetic Rats ◽  
Morris Water Maze Test ◽  
Mitochondrial Morphology ◽  
Underlying Mechanisms ◽  
And Function ◽  
Energy Failure

Background/Aims: Mitochondrial perturbation is a well-established cause of cognitive decline, but as yet it is unclear how mitochondria-associated neuronal abnormalities in type 1 diabetic (T1DM) brain contribute to cognitive decline. Methods: The streptozotocin (STZ)-induced mouse model of T1DM was used. The Morris water maze test was applied to assess the effect of T1DM on learning and memory. We detected changes in mitochondrial morphology, function and dynamics. Furthermore, we employed metabolomic analysis to reveal the underlying mechanisms of mitochondrial perturbation which contribute to cognitive decline. Results: Our results show that T1DM impairs mitochondrial dynamics, morphology and function in neurons, associated with a decline in cognitive ability. Metabolomic analyses revealed that T1DM mainly affects metabolic pathways involved in mitochondrial energy failure and impairs the antioxidative system. Conclusion: These results lay the basis for understanding the underlying mitochondria-associated causes of T1DM-associated cognitive decline and may provide a potential treatment strategy for this condition in future.

In vivo imaging of intracellular Ca2+ after muscle contractions and direct Ca2+ injection in rat skeletal muscle in diabetes

2013 ◽  
Vol 305 (6) ◽  
pp. R610-R618 ◽  
Author(s):  
Hiroaki Eshima ◽  
Yoshinori Tanaka ◽  
Takashi Sonobe ◽  
Tadakatsu Inagaki ◽  
Toshiaki Nakajima ◽  
...  
Keyword(s):  
Diabetic Rats ◽  
Buffering Capacity ◽  
Muscle Contractions ◽  
Rat Skeletal Muscle ◽  
Protein Levels ◽  
Intracellular Ca ◽  
Male Wistar Rats ◽  
Healthy Control

The effects of muscle contractions on the profile of postcontraction resting intracellular Ca2+ ([Ca2+]i) accumulation in Type 1 diabetes are unclear. We tested the hypothesis that, following repeated bouts of muscle contractions, the rise in resting [Ca2+]i evident in healthy rats would be increased in diabetic rats and that these changes would be associated with a decreased cytoplasmic Ca2+-buffering capacity. Adult male Wistar rats were divided randomly into diabetic (DIA; streptozotocin, ip) and healthy control (CONT) groups. Four weeks later, animals were anesthetized and spinotrapezius muscle contractions (10 sets of 50 contractions) were elicited by electrical stimulation (100 Hz). Ca2+ imaging was achieved using Fura-2 AM in the spinotrapezius muscle in vivo (i.e., circulation intact). The ratio (340/380 nm) was determined from fluorescence images following each set of contractions for estimation of [Ca2+]i. Also, muscle Ca2+ buffering was studied in individual myocytes microinjected with 2 mM Ca2+ solution. After muscle contractions, resting [Ca2+]i in DIA increased earlier and more rapidly than in CONT ( P < 0.05 vs. precontraction). Peak [Ca2+]i in response to the Ca2+ injection was significantly higher in CONT (25.8 ± 6.0% above baseline) than DIA (10.2 ± 1.1% above baseline). Subsequently, CONT [Ca2+]i decreased rapidly (<15 s) to plateau 9–10% above baseline, whereas DIA remained elevated throughout the 60-s measurement window. No differences in SERCA1 and SERCA2 (Ca2+ uptake) protein levels were evident between CONT and DIA, whereas ryanodine receptor (Ca2+ release) protein level and mitochondrial oxidative enzyme activity (succinate dehydrogenase) were decreased in DIA ( P < 0.05). In conclusion, diabetes impairs resting [Ca2+]i homeostasis following muscle contractions. Markedly different responses to Ca2+ injection in DIA vs. CONT suggest fundamentally deranged Ca2+ handling.

scholarly journals Identification and functional characterization of malignant hyperthermia mutation T1354S in the outer pore of the Cavα1S-subunit

2010 ◽  
Vol 299 (6) ◽  
pp. C1345-C1354 ◽  
Author(s):  
Antonella Pirone ◽  
Johann Schredelseker ◽  
Petronel Tuluc ◽  
Elvira Gravino ◽  
Giuliana Fortunato ◽  
...  
Keyword(s):  
Malignant Hyperthermia ◽  
Genetic Locus ◽  
Functional Characterization ◽  
Malignant Hyperthermia Susceptibility ◽  
Loop Region ◽  
Whole Cell Patch Clamp ◽  
Voltage Dependent ◽  
Intracellular Ca ◽  
And Function ◽  
The Impact

To identify the genetic locus responsible for malignant hyperthermia susceptibility (MHS) in an Italian family, we performed linkage analysis to recognized MHS loci. All MHS individuals showed cosegregation of informative markers close to the voltage-dependent Ca2+ channel (CaV) α1S-subunit gene (CACNA1S) with logarithm of odds (LOD)-score values that matched or approached the maximal possible value for this family. This is particularly interesting, because so far MHS was mapped to >178 different positions on the ryanodine receptor (RYR1) gene but only to two on CACNA1S. Sequence analysis of CACNA1S revealed a c.4060A>T transversion resulting in amino acid exchange T1354S in the IVS5-S6 extracellular pore-loop region of CaVα1S in all MHS subjects of the family but not in 268 control subjects. To investigate the impact of mutation T1354S on the assembly and function of the excitation-contraction coupling apparatus, we expressed GFP-tagged α1ST1354S in dysgenic (α1S-null) myotubes. Whole cell patch-clamp analysis revealed that α1ST1354S produced significantly faster activation of L-type Ca2+ currents upon 200-ms depolarizing test pulses compared with wild-type GFP-α1S (α1SWT). In addition, α1ST1354S-expressing myotubes showed a tendency to increased sensitivity for caffeine-induced Ca2+ release and to larger action-potential-induced intracellular Ca2+ transients under low (≤2 mM) caffeine concentrations compared with α1SWT. Thus our data suggest that an additional influx of Ca2+ due to faster activation of the α1ST1354S L-type Ca2+ current, in concert with higher caffeine sensitivity of Ca2+ release, leads to elevated muscle contraction under pharmacological trigger, which might be sufficient to explain the MHS phenotype.

scholarly journals The Role of Sechium edule Fruits Ethanolic Extract in Insulin Production and Malondialdehyde Level in Stz-Induced Diabetic Rat

2019 ◽  
Vol 4 (1) ◽  
pp. 11
Author(s):  
Betty Lukiati ◽  
Nugrahaningsih Nugrahaningsih ◽  
Siti Nur Arifah
Keyword(s):  
Ethanolic Extract ◽  
Positive Control ◽  
Negative Control ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Sechium Edule ◽  
Liver And Pancreas ◽  
Group A ◽  
Kidney Liver

The objectives of this research were to examine the effect of Sechium edule ethanolic extract in insulin and Malondialdehyde (MDA) levels in streptozotocin (STZ) induced diabetic rats. Type 1 diabetic rat were obtained by intraperitonially injected with multiple low dose STZ (MLD-STZ) 20 mg/kgBW for 5 days. The animals were divided into 5 groups: untreated rats in group (K) were considered as negative control, MLD-STZ induced type 1 diabetic rats in group (S) were considered as positive control. In another 3 group (A, B, C) type 1 diabetic rats were orally treated with three doses of S. edule ethanolic extract (14, 28, 42 mg/kg BW) for 7 days. The animals were sacrificed in two days after last treatment, serum were collected for measuring of the insulin concentration by ELISA method. Level of MDA on kidney, liver and pancreas were measured by TBA method. The treatment with S. edule ethanolic extracts unable to increase of insulin yet but the treatment with 42 mg/kg BW of S. edule ethanolic extract showed significantly decreased MDA levels on liver but not significant on kidney and pancreas.

scholarly journals SLC40A1 mediates ferroptosis and cognitive dysfunction in type 1 diabetes

2020 ◽  
Author(s):  
Lijun Hao ◽  
Jun Mi ◽  
Liping Song ◽  
Yinnan Guo ◽  
Yanli Li ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Cognitive Dysfunction ◽  
Low Frequency ◽  
Latency Period ◽  
Diabetic Rats ◽  
Blood Oxygenation ◽  
Morris Water Maze Test ◽  
Diabetic Rat ◽  
Dependent Signal

Abstract Objective: Cognitive dysfunction often accompanies diabetes. Both hypoglycemia and hyperglycemia cause cognitive dysfunctions. However, the underlying pathophysiology remains unclear. Recent evidence show that ferroptosis primarily triggers nerve cell death, Alzheimer's disease (AD), Huntington’s disease (HD), and Parkinson's disease (PD). We purposed to investigate whether ferroptosis is a vital pathogenic pathway in diabetes-induced cognitive dysfunction. Methods and results: Type 1 diabetic rat model was created by intraperitoneal injection of streptozotocin (STZ). Significant cognitive dysfunction was observed in the diabetic rats as evidenced by increase in latency period to find a hidden platform and decreased cumulative time spent in the target quadrant in the Morris water maze test. We detected the amplitude of low-frequency fluctuation (ALFF) of the BOLD (Blood Oxygenation Level-Dependent) signal using resting-state functional magnetic resonance imaging (rs-fMRI). Consequently, we found that the ALFF values, as well as the T2 relaxation time of the bilateral hippocampus, were reduced in Type 1 diabetic rats. We detected Fe2+ level and lipid peroxidation products (MDA and 4-HNE) in the hippocampus. Mitochondria and neuron injury in the STZ-induced diabetic rats were determined using a Transmission Electron Microscope and Nissl body staining. Iron overload and ferroptosis were detected in the hippocampus. Furthermore, mRNA microarray analysis revealed 201 dysregulated mRNAs in STZ-induced type 1 diabetes (T1D). Pathway enrichment analyses indicated that differentially expressed mRNAs associated-coding genes were associated with ferroptosis. Among ferroptosis signaling pathway genes, Slc40a1 gene (ferroportin) was downregulated.Conclusion: We show that ferroptosis is associated with diabetic cognitive dysfunction and Slc40a1 mediates ferroptosis in Type 1 diabetes.

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